The Goal
Chemical probes are small molecules that perturb the function of their biological target. These probes can be powerful tools for studying proteostasis. However, not all reported molecules have been evaluated for target selectivity, potency and/or metabolism at the same level of scrutiny. Often, these probes might have many possible cellular targets, making it difficult to attribute their effects to a specific protein. The Proteostasis Pharmacology subgroup is working to promote the rigorous use of chemical probes, with the goal of accelerating the discovery of new therapeutics for neurodegenerative diseases.
The Chemical Probes Annotation Team
During the past two years, the Proteostasis Consortium team, including members of the Finkbeiner (University of California San Francisco and Gladstone Institute), Finley (Harvard Medical School), Frydman (Stanford), Gestwicki (UCSF), Kelly (Scripps Research), and Morimoto (Northwestern University) laboratories have been working together to review chemical probes. This work relies heavily on the expert work of the team at ChemicalProbes.org, as well as the expertise of the various laboratories and member of the broader research and drug discovery communities.
Methods and Background
As a first step, we selected compounds that have been evaluated in ChemicalProbes.org and that target proteins or pathways within the Proteostasis Network (e.g., protein folding, trafficking, quality control, degradation and the stress responses). Using the links provided below, you can access information about each compound, including its known off-targets and what concentration it should be used at in cellular and animal experiments. This information also includes expert rankings, which will help guide your decisions about which compounds to use. The Proteostasis Consortium will continue to expand this collection and serve as a clearinghouse for exchange of information about the proper use of chemical probes for proteostasis targets.
How should you use this information? Before designing your experiment, check the available information to help choose the best chemical probe for your individual experiment. For example, if you want to perform an experiment in a rodent model, be sure that the formulation, dose and frequency will ensure that the target is inhibited over the course of your experiment, without unintended side effects or toxicity. Most small molecules will have unintended targets (termed off-targets), especially if used at high concentrations. By designing good experiments, you can avoid making incorrect conclusions about the role of a specific target.
Current Chemical Probe Information
Chemical Probes evaluated by ChemicalProbes.org
Organized by proteostasis pathway and target
Folding / Trafficking / Quality Control
Hsp90
AUY922 (https://www.chemicalprobes.org/luminespib?q=Hsp90)
BIIB021 (https://www.chemicalprobes.org/biib021?q=Hsp90)
Onalespib (https://www.chemicalprobes.org/onalespib?q=Hsp90)
p97
CB-5083 (https://www.chemicalprobes.org/cb-5083?q=p97)
NMS-873 (https://www.chemicalprobes.org/nms-873?q=p97)
Sec61
cotransin (https://www.chemicalprobes.org/cotransin?q=SEC61)
Degradation
UBA1
TAK243 (https://www.chemicalprobes.org/tak-243)
ABP3 (https://www.chemicalprobes.org/abpa3)
UBA3
pevonedistat (https://www.chemicalprobes.org/pevonedistat)
USP1
ML323 (https://www.chemicalprobes.org/ml323?q=USP)
Immunoproteasome
KZR- 504 (https://www.chemicalprobes.org/kzr-504?q=proteasome)
mTor
rapamycin (https://www.chemicalprobes.org/rapamycin?q=rapamycin)
AZD-2014 (https://www.chemicalprobes.org/azd2014?q=rapamycin)
Mdm2
RO5353 (https://www.chemicalprobes.org/ro5353?q=MDM2)
MD-244 (https://www.chemicalprobes.org/md-224?q=MDM2)
AMG232 (https://www.chemicalprobes.org/amg232?q=MDM2)
RO2468 (https://www.chemicalprobes.org/ro2468?q=MDM2)
RG7112 (https://www.chemicalprobes.org/rg7112?q=MDM2)
GID4
PFI-7 (https://www.chemicalprobes.org/pfi-7?q=Gid4)
Stress Responses
Ire1
AMG-18 (https://www.chemicalprobes.org/amg-18?q=IRE1)
KEAP1-Nrf2
KI-696 (https://www.chemicalprobes.org/ki-696)
Page last updated: 3/15/2023
